PIM1 is a Poor Prognostic Factor for and Potential Therapeutic Target in Serous Carcinoma of the Endometrium.

Serous carcinoma (SC) is an aggressive histologic type of endometrial carcinoma (EMC) with a poor prognosis. The development of novel therapeutics for SC is an important issue. PIM1 is a serine/threonine kinase involved in various cellular functions, such as cell cycle progression, apoptosis, and transcriptional activation via the phosphorylation of many target proteins, including MYC. PIM1 is overexpressed in several cancers and has been associated with treatment-resistance. We investigated the expression and function of PIM1 in EMC, particularly SC. Immunohistochemical analysis in 133 EMC cases [103 endometrioid carcinomas (EC) and 30 SC] revealed the significantly stronger expression of PIM1 in SC than in EC and significantly shorter survival of patients with overexpression of PIM1 in all EMC cases, as well as in only SC cases. A multivariate analysis identified overexpression of PIM1 as an independent prognostic factor. The knockdown of PIM1 by siRNA in the SC cell line, ARK1, decreased the expression of phosphorylated MYC and reduced proliferation, migration, and invasion. The PIM1 inhibitor, SGI-1776, reduced cell viability in SC cell lines (ARK1, ARK2, and SPAC1L) with IC50 between 1 and 5 µM. SGI-1776 also reduced the migration and invasion of ARK1 cells. Moreover, the oral administration of SGI-1776 significantly suppressed subcutaneous ARK1 xenograft tumor growth in nude mice without impairing health. These results indicate that PIM1 is involved in the acquisition of aggressiveness and suggest the potential of PIM1 as a novel therapeutic target and SGI-1776 as a therapeutic agent for SC.

"Welcome to OBGYN World!" A novel recruitment event for medical students organized by the Japan Society of Obstetrics and Gynecology.

"Welcome to OBGYN World!" A novel recruitment event for medical students organized by the Japan Society of Obstetrics and Gynecology. Since 2012, the number of doctors in Japan who specialize in obstetrics and gynecology has shown a decreasing trend. To increase the number of doctors majoring in obstetrics and gynecology, the Japanese Trainees in Obstetrics and Gynecology subcommittee developed a new recruitment event called Welcome to OBGYN World! (WOW!); the aim of this event was to focus on lower grades of medical students. The present report describes the content of WOW! and the results of a post-event questionnaire administered to participating students and tutors. WOW! was held online in order to avoid the risk of Coronavirus Disease 2019 infection for participants. Sixty of the 82 medical schools nationwide (73.2%) participated in this event. Overall, there were 285 participating students, ranging from first to fourth grade in medical school, and 106 tutors were involved to teach material at the event. In the post-event questionnaire survey, 97.6% (248/254) and 100% of the participants stated they now had a high degree of interest in obstetrics and gynecology and found the specialty attractive, respectively. Furthermore, 93.6% (90/94) of the tutors stated that WOW! had helped recruitment activities in their universities. Based on this outcome, members of the Japanese Trainees of Obstetrics and Gynecology subcommittee will now try to increase the number of doctors specializing in obstetrics and gynecology by holding WOW! annually.

A survey of Japanese interns to prepare for mandatory clinical training in obstetrics and gynecology.

AIM: Obstetrics and gynecology (Ob/Gyn) training became compulsory for Japanese physician interns from April 2020 to improve medical competence in treating women's diseases. This study aims to understand the Ob/Gyn training needs of postgraduate year 1-2 physicians (interns) and thereby improve training efficiency. METHODS: This study was administered to interns at Ob/Gyn training facilities from December 2019 to February 2020. An original questionnaire was used to evaluate their assessment of training needs. In analyses, interns were categorized according to whether they were willing to major in Ob/Gyn. RESULTS: Of the 1154 participants, 163 (14.1%) would major in Ob/Gyn (Ob/Gyn applicants) and 967 (83.8%) would not (non-Ob/Gyn applicants). At the time of the survey, 634 (54.9%) had rotated in Ob/Gyn, 253 (21.9%) planned to rotate, and 267 (23.1%) chose not to rotate. The two most favorable training experiences were "experience in surgical procedures" (81/141, 57.4%) and "wide treatment areas covered by Ob/Gyn" (78/141, 55.3%) among the Ob/Gyn applicants, and "specificity of women's treatment" (308/488, 63.1%) among the non-Ob/Gyn applicants. CONCLUSIONS: Ob/Gyn applicants and non-Ob/Gyn applicants differed in their assessment of Ob/Gyn rotations. It is crucial to provide medical training based on interns' needs to improve their skills for treating female patients.

Anti-tumor effect of Wasabi component, 6-(methylsulfinyl) hexyl isothiocyanate, against endometrial carcinoma cells.

PURPOSE: Wasabi is a traditional plant seasoning with an anti-septic function. Recent studies revealed several functions of Wasabi, such as anti-inflammation; however, the anti-tumor effect against endometrial carcinoma (EMC) cells has not been examined. In the present study, we investigated the anti-tumor effect of 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC), a major chemical compound of Wasabi, against various EMC cell lines in vitro and in vivo. METHODS: The effect of 6-MITC on cell viability was measured by the WST-1 assay in EMC and HUVEC cells. The impact of 6-MITC oral administration in nude mice was measured to assess the growth of the EMC xenograft and natural killer (NK) cell activity in the spleen. RESULTS: The addition of 6-MITC suppressed the proliferation of EMC cells (Ishikawa, HEC265, HEC108, KLE, and HEC1B) dose-dependently, but not HUVEC cells. 6-MITC (5 µM) enhanced the cisplatin sensitivity of EMC cells. 6-MITC induced apoptosis in a dose-dependent fashion in EMC cells other than HEC1B cells and was associated with increased expression of cleaved-caspase3 and decreased expression of BCL2. Oral administration of 6-MITC (2 and 4 µmol/kg) to Ishikawa and HEC1B xenografting mice resulted in a reduced tumor volume compared with the control (P < 0.05, 4 µmol/kg). Immunohistochemical staining of resected tumors revealed increased expression of Ki-67 and reduced cleaved-caspase3. Furthermore, 6-MITC treatment enhanced NK cell activity, especially when administered before tumor xenografting. CONCLUSION: These results indicate that 6-MITC has a marked anti-tumor effect against EMC cells and a novel effect to enhance NK cell activity. These effects suggest the therapeutic potential of 6-MITC.

Establishment of a novel model of endometriosis-associated ovarian cancer by transplanting uterine tissue from Arid1a/Pten knockout mice.

Although endometriosis is primarily benign, it has been identified as a risk factor for endometriosis-associated ovarian cancer (EAOC). Genetic alterations in ARID1A, PTEN, and PIK3CA have been reported in EAOC; however, an appropriate EAOC animal model has yet to be established. Therefore, the present study aimed to create an EAOC mouse model by transplanting uterine pieces from donor mice, in which Arid1a and/or Pten was conditionally knocked out (KO) in Pax8-expressing endometrial cells by the administration of doxycycline (DOX), onto the ovarian surface or peritoneum of recipient mice. Two weeks after transplantation, gene KO was induced by DOX and endometriotic lesions were thereafter removed. The induction of only Arid1a KO did not cause any histological changes in the endometriotic cysts of recipients. In contrast, the induction of only Pten KO evoked a stratified architecture and nuclear atypia in the epithelial lining of all endometriotic cysts, histologically corresponding to atypical endometriosis. The induction of Arid1a; Pten double-KO evoked papillary and cribriform structures with nuclear atypia in the lining of 42 and 50% of peritoneal and ovarian endometriotic cysts, respectively, which were histologically similar to EAOC. These results indicate that this mouse model is useful for investigating the mechanisms underlying the development of EAOC and the related microenvironment.

Clinical characteristics of a novel "Type 3" vasa previa: case series at a single center.

OBJECTIVE: Vasa previa is a condition in which fetal blood vessels are located on fetal membranes within 2 cm of the internal cervical os. Vasa previa has been classified into two types: Type 1, in which vessels connect a velamentous umbilical cord to the placenta, and Type 2, in which vessels connect the lobes of a bilobed placenta or the placenta to a succenturiate lobe. However, there are also atypical cases that cannot be classified into these two types. These cases are manifested by a center or marginal cord insertion with a normal shaped placenta, and fetal vessels were also located on membranes around the internal cervical os. These cases were recently proposed as Type 3 vasa previa. The present study investigated the incidence of Type 3 vasa previa and elucidated differences in clinical and ultrasonographical characteristics between traditional types and Type 3. METHODS: This was a single-center observational study using a cohort of all vasa previa cases between January 2010 and April 2020. RESULTS: Among 8,723 deliveries, there were 14 cases (0.16%) of vasa previa, all of which were diagnosed prenatally by US, not after vaginal delivery or CS. There were 9 (64%), 0, and 5 (36%) cases of Types 1, 2, and 3, respectively. All 5 Type 3 cases had only one fetal aberrant vessel of vasa previa, while 6 out of 9 Type 1 cases (67%) had two or more aberrant vessels. Seven Type 1 cases (78%) possessed two or more known risk factors, such as velamentous cord insertion, whereas all Type 3 cases only had one. Difficulties were associated with diagnosing two out of the 14 cases of vasa previa using routine transvaginal ultrasonography (TVUS). In these cases, the aberrant fetal vessel of vasa previa was only one vein with a thin wall that was not clearly visualized by gray-scale TVUS as well as slow flow that was easily misread by color-Doppler. These cases were ultimately diagnosed as vasa previa based on non-pulsatile flow detected by color and pulsed Doppler. CONCLUSIONS: The present results suggest that Type 3 may account for a large proportion of vasa previa cases. Most Type 3 cases may present with only one fetal aberrant vessel of vasa previa and fewer risk factors, suggesting that the diagnosis of vasa previa may be more challenging in Type 3 cases than in the other types. Vasa previa with a venous vasa previa needs to be considered because of the difficulties associated with an antenatal diagnosis due to unclear imaging of the vasculature or the lack of specific color Doppler flow patterns. Pulsed Doppler imaging may be helpful for the diagnosis of these cases.